The primary focus of this laboratory is to evaluate, characterize, and quantitate the interaction of specific lipoproteins and apolipoproteins with certain cell types. By studying the effects of the lipoproteins on the lipid and lipo-protein metabolism of fibroblasts, macrophages, and hepatocytes from normal and dyslipidemic subjects, and understanding of normal lipoprotein physiology as well as the pathophysiology of the dyslipidemias will emerge. The coordinate control of cholesterol synthesis through HMG-CoA reductase, cholesteryl ester hydrolysis by both acid and neutral cholesteryl ester hydrolyses, and the number and affinity of the different lipoprotein receptors in cellular membranes is of central importance in our research program. Using these techniques, the lipids, lipoproteins and their cellular metabolism have been evaluated in a number of disease states: Familial Hypercholesterolemia, Abetalipoproteinemia, Wolman's Disease, Cholesteryl Ester Storage Disease, Tangier Disease, and Erdheim-Chester Disease. In addition, clinical studies in the treatment of these disorders are in progress. We have determined that adult human liver expresses distinct recognition sites for apolipoproteins A-I, E, and B. By analyzing the hepatic receptors for these apolipoproteins in several dyslipidemic states, distinct genetic and physiologic control of these receptors has been demonstrated. Cellular abnormalities in cholesteryl ester by hydrolysis and its relation with dyslipoproteinemia has also been explored. In addition to examining perturbations in cellular recognition and metabolism of lipoproteins, potential abnormalities in the biologic function of specific lipoproteins and apolipoproteins have been evaluated. Pseudo familial hypercholesterolemia cannot be ascribed to aberrant apoB biologic function in these assays but Erdheim-Chester Disease may reflect enhanced macrophage uptake of triglyceride-rich lipoproteins. Finally, the antibiotic neomycin has been found to be a safe, well-tolerated hypocholesterolemic agent in the treatment of type II hyperlipoproteinemia.